Influenza virus is 1 of the most important human pathogens accounting for widespread morbidity and mortality. Influenza virus is currently classified as a NIAID Biodefense Category C priority pathogen, a status that may be upgraded due to the recent emergence of a highly virulent strain of avian influenza virus in Thailand, Vietnam, North Korea and other Asian countries. On average, more than 35,000 people per year die from influenza virus infection in the United States. Highly virulent strains of influenza virus can rapidly achieve pandemic status in which millions or even tens of millions of people can die. The potential for human pathogenic strains to arise, via crossover from birds or other species, then reassortment, is well established. Both the World Health Organization and the Centers for Disease Control and Prevention have declared that it is only a matter of time before the next worldwide flu pandemic. The new strains of bird flu appear to be resistant to amantadine and related influenza drugs. Hemagglutinin, the membrane fusogenic envelope glycoprotein of influenza viruses, shares several common structural features with the fusion proteins of an otherwise diverse group of enveloped RNA viruses. These conserved structural domains are important in influenza virus infection, entry and pathogenesis. The studies proposed will determine whether synthetic peptides corresponding to motifs of the influenza virus glycoproteins can interfere with fusion/infectivity by influenza viruses. The premise of this STTR application is that because of salient similarities between the fusion proteins of influenza virus and other RNA viruses that a body of prior research can be used to guide studies of drug development against this serious public health threat and potential bioterrorism agent. Specific Aim 1 is to identify peptides corresponding to sequences in influenza virus glycoproteins that inhibit virus infectivity. Molecular modeling and algorithms, including the Wimley-White interfacial hydrophobicity scale, will be used to identify candidate peptides. Specific Aim 2 is to evaluate the efficacy of lead peptides in ferrets, the small animal model that best recapitulates human influenza virus pathogenesis. Specific Aim 3 is to elucidate the steps in the virus replication cycle at which active peptides inhibit influenza virus infection. Specific Aim 4 is to optimize peptides showing antiviral activity in ferrets for inhibition of influenza virus infectivity by modifications that increase stability, solubility, and target the peptides to intracellular compartments. The studies proposed in this application will address an urgent public health and biodefense need for new drugs that are effective against influenza viruses. [unreadable] [unreadable]